Despite more than two decades of extensive sales in the dietary supplements market, (−)-hydroxycitric acid (HCA) (typically extracted from Garcinia cambogia. G. atroviridis, G. indica and related species) and its various salts continues to lack delivery methods leading to adequate dispersion of the HCA in the gut as described below using the extensive record of weight loss trials as examples. Beverage deliveries have not proven successful due to low amounts of active, lactone formation and binding to other ingredients. Tablet deliveries provide poor dispersion as shown by documented experience. A liquid-filled hard shell delivery was tried, but never made it into sustained commercialization and was abandoned in part due to costs and in part due to the requirement for excessively large (“000”) capsules. Only two soft gelatin formats presently seem to be available commercially. Both simply coat HCA salts with fats (coconut and/or palm oil) and place a relatively small amount of the HCA salt, again, in a very large capsule. This approach duplicates many or all of the limitations of tablet and ordinary capsule deliveries.
Free (−)-hydroxycitric acid, calcium, magnesium and potassium salts of HCA and poorly characterized mixtures of two or more of these minerals, usually substantially contaminated with sodium—and, sometimes, even free chloride ion with only the sodium has been removed, currently exist on the American market. Calcium/sodium salts have been sold widely since at least as early as 1992. Most of the HCA sold to date consists of calcium salts of varying degrees of purity and, more recently, of poorly characterized calcium and potassium mixtures. For instance, the currently best selling HCA salt (potassium-calcium hydroxycitrate) typically contains ≥10 percent impurities and the product specification allows for approximately 25 percent±variations in the mg/gram of the potassium and calcium cations. (Shara M, Ohia S E, Schmidt R E, Yasmin T, et al. Physico-chemical properties of a novel (−)-hydroxycitric acid extract and its effect on body weight, selected organ weights, hepatic lipid peroxidation and DNA fragmentation, hematology and clinical chemistry, and histopathological changes over a period of 90 days. Mol Cell Biochem. 2004 May; 260(1-2):171-86.) Safety issues have been raised with regard to the free acid and lactone forms of HCA due to their strong chelating properties and the risk of excessive loss of zinc from the body, a concern especially important to males both in puberty and in the later stages of life.
HCA was very extensively studied by Hoffman-La Roche. Animal tests to establish the appetite suppressing effects of HCA found that a single large oral dose or two divided oral doses totaling approximately one-fourth the size of the single dose resulted in a 10% or greater reduction in food consumption in experimental animals fed a high-sugar diet. (Minimum doses were 2.63 mmoles/kg once per day or 0.33 mmoles/kg twice per day either one hour before meals or four hours after, but not after the last meal of the day.) This result continued over many weeks, but in no case beyond approximately seven weeks, with the chronic ingestion of HCA. The appetite control mechanism of HCA was said to not involve any conditioned aversion to food, i.e., HCA does not alter taste, cause gastric distress or illness, etc. Rather, this control was thought to stem from the increased production of glycogen and/or stimulation of glucoreceptors in the liver, either of which results in early satiety through signals sent to the brain via the vagus nerve. It has now been demonstrated experimentally that the Roche position that HCA suppresses appetite through vagal afferents associated with the liver almost certainly is mistaken. In an animal trial in which the hepatic branch of the vagus was severed (hepatic branch vagotomy), there was no significant effect found with this surgery in comparison with controls. (Leonhardt M, Hrupka B J, Langhans W. Subdiaphragmatic vagal deafferentation fails to block the anorectic effect of hydroxycitrate. Physiol Behav. 2004 Sep. 15; 82(2-3):263-8.)
Human research has provided, at best, only weak support for the Roche satiety findings, which were based on animal trials and mostly restricted diets, for instance, based predominantly on glucose. Early satiety with meals has been found only under very limited conditions. Ingesting tablets or capsules, even when there was significant weight loss, has not led to significantly advanced satiety. For instance, although 1,200 mg HCA daily given as tablets (2×400 mg 50% material as Citrin® calcium hydroxycitrate taken 3 times daily before meals) for 12 weeks led to significant weight loss, there was no significant change in food intake. The findings were 3.7±3.1 kg active versus 2.4±2.9 kg placebo. Over a 3-month period, these results of less than a pound of additional weight loss per month are hardly impressive; however, the difference is significant. (Mattes R D, Bormann L. Effects of (−)-hydroxycitric acid on appetitive variables. Physiol Behav. 2000 Oct. 1-15; 71(1-2):87-94.)
A more recent trial that utilized a diet normal in caloric intake, but reduced in fat and employing prepared meals, enforced exercise, and visual inspection of capsule consumption found significant weight loss, but mealtime satiety was increased over a period of many weeks rather than days. (Preuss H G, Bagchi D, Bagchi M, Rao C V, Dey D K, Satyanarayana S. Effects of a natural extract of (−)-hydroxycitric acid (HCA-SX) and a combination of HCA-SX plus niacin-bound chromium and Gymnema sylvestre extract on weight loss. Diabetes Obes Metab. 2004 May; 6(3):171-80.) At the end of eight weeks, appetite was decreased by approximately 15.6% in the group consuming 2,800 mg/HCA per day in capsules and by 21.2% in those consuming this amount of HCA plus other ingredients. Placebo experienced no reduction in appetite. Obviously, a certain percentage of the change in appetite in the active arms at the end of eight weeks can be attributed to weight loss rather than satiety per se. More telling, a trial described below using the same HCA source at only 900 mg/day, but delivered differently, reduced appetite by 15-30% in a mere two weeks.
The reductions in appetite and the other findings in the Preuss study also appear to be inflated by the failure to properly blind the trail. Put simply, the placebo used in the trial, microcrystalline cellulose, is a light filler having a bulk density of between 0.2 and 0.4 g/cc, whereas a calcium-potassium HCA salt has a bulk density of between 0.7 and 0.9 g/cc. Even in opaque capsules, it immediately would have been obvious to all involved which capsules contained placebo and which contained the actives. The failure of the blinding answers many of the questions that have been raised regarding this study (somewhat misleadingly published as several papers over a two-year period) conducted entirely in India under Indian conditions. For instance, despite boxed meals and enforced/supervised exercise in previously sedentary subjects, in the placebo arm there either was no benefit or even a trend upward for LDL, triglycerides and total cholesterol, whereas HDL trended downward. Bodyweight in placebo barely budged at either 4 or 8 weeks. In effect, there was no placebo response despite major interventions, any one of which normally produces significant results in LDL, HDL, triglycerides, total cholesterol, and body weight. To take but one parameter, the failure to show weight loss in placebo under these experimental conditions is out of line with the great preponderance of published studies. (Truby H, Baic S, deLooy A, Fox K R, et al. Randomised controlled trial of four commercial weight loss programmes in the UK: initial findings from the BBC “diet trials”. BMJ. 2006 Jun. 3; 332(7553):1309-14.) Even taking the study at face value, the reductions in appetite reported were small and required many weeks to become important.
Human trials with HCA showing the rapid onset of meal-linked satiety are limited to only one study. Current HCA products have been shown to induce meal satiety (as opposed to reducing snacking) within a reasonable time period of days rather than weeks only under the very limited condition of being dissolved in 100 ml tomato juice just prior to ingestion timed approximately an hour before lunch and supper, then two hours after the evening meal to reduce snacking. In a trial published in 2002, although food intake decreased 15-30% there was no significant weight loss over a 2-week period. (Westerterp-Plantenga M S, Kovacs E M. The effect of (−)-hydroxycitrate on energy intake and satiety in overweight humans. Int J Obes Relat Metab Disord. 2002 June; 26(6):870-2.) The researchers themselves noted the problematic nature of HCA delivery by way of the observation “Prevention of degradation and bio-availability was documented.” The satiety found in this study using much smaller amounts of HCA than in Preuss 2004 (900 mg vs. 2800 mg) not only appeared far more quickly, but was more powerful than that reported in the 2004 Indian study even at the end of the 8 week trial.
The foregoing studies are representative. The only reasonable conclusion that can be drawn from the literature available on HCA in humans is that there is little impact on meal satiety when the compound is delivered via capsules or tablets if the relevant period is counted in days rather than weeks. To date, satiety has been demonstrated in humans only when HCA is dissolved and delivered in a substantial amount of tomato juice approximately an hour before meals. Capsules and tablets have proved to be ineffective for inducing meal satiety. Indeed, despite the Indian trial described above and published as several papers in 2004 and 2005, two of the leading American researchers in the field of bariatrics in 2007 continued to express skepticism regarding the viability of HCA as a diet product. (Bray G A, Greenway F L. Pharmacological treatment of the overweight patient. Pharmacol Rev. 2007 June; 59(2):151-84.)
Delivering meal satiety with HCA under the only approach shown to work, i.e., mixing in a large volume of tomato juice just before consuming 60 minutes prior to meals, is extremely onerous. The components of this approach include a) preventing degradation of the HCA, b) insuring the complete release of the HCA, and c) insuring bioavailability of the HCA. Degradation is a major issue. Not one of the proposed ready-to-drink HCA preparations or HCA “waters” that have been marketed has succeeded, in large part because of degradation. HCA, as is well established, very readily binds to gums, fibers and pectins. It also binds to many phytochemicals, such catechins and polyphenols more generally. Leaving HCA in prepared beverage preparations, especially those that have been heat pasteurized, encourages these reactions and also induces the rapid formation of the HCA lactone. The lactone is almost totally ineffective for satiety and other health purposes. (Lowenstein J M, Brunengraber H. Hydroxycitrate. Methods Enzymol. 1981; 72:486-97.) However, the lactone does have at least one negative impact—it has a type of toxicity, probably due to its binding zinc and leading to its excretion from the body. The lactone is labile to the acid, so the chelation most likely is due to the free acid. (Burdock G, Soni M, Bagchi M, Bagchi D. Garcinia cambogia toxicity is misleading. Food Chem Toxicol. 2005 November; 43(11):1683-4; author reply 1685-6. Erratum in: Food Chem Toxicol. 2007 March; 45(3):515.) Studies by other researchers utilizing fully reacted HCA salts have found no toxicities.
The other two issues of complete release and bioavailability, similarly, pose daunting challenges. Westerterp-Plantenga and Kovacs chose tomato juice as a vehicle precisely because its pH would insure that the HCA salt was fully dissolved. By using a relatively high volume vehicle, they also insured that the dissolved salt would be exposed to any possible receptors in the stomach and intestine as well as allowing for better uptake. In this sense, their approach replicates the usually successful delivery of HCA by gavage. It is not accidental that no one has been able to duplicate Westerterp-Plantenga and Kovacs' results by means of other forms of delivery until now.
As demonstrated by the foregoing, the issues of degradation, complete release and bioavailability are not successfully addressed by current HCA deliveries. It clearly is desirable to find better solutions. The Inventors propose a solution that can be implemented via soft gelatin capsules, liquid-filled hard shell capsules and a number of other dosage forms.